Pain medicine training resources: Module 2

Update in: Weinstein EJ, Levene JL, Cohen MS, et al. Local anaesthetics and regional anaesthesia versus conventional analgesia for preventing persistent postoperative pain in adults and children. Cochrane Database Syst Rev. 2018;4(4):CD007105.

Abstract
Background and objectives: This second European Federation of Neurological Societies Task Force aimed at updating the existing evidence about the pharmacological treatment of neuropathic pain since 2005.

Methods: Studies were identified using the Cochrane Database and Medline. Trials were classified according to the aetiological condition. All class I and II randomized controlled trials (RCTs) were assessed; lower class studies were considered only in conditions that had no top-level studies. Treatments administered using repeated or single administrations were considered, provided they are feasible in an outpatient setting.

Results: Most large RCTs included patients with diabetic polyneuropathies and post-herpetic neuralgia, while an increasing number of smaller studies explored other conditions. Drugs generally have similar efficacy in various conditions, except in trigeminal neuralgia, chronic radiculopathy and HIV neuropathy, with level A evidence in support of tricyclic antidepressants (TCA), pregabalin, gabapentin, tramadol and opioids (in various conditions), duloxetine, venlafaxine, topical lidocaine and capsaicin patches (in restricted conditions). Combination therapy appears useful for TCA-gabapentin and gabapentin-opioids (level A).

Conclusions: There are still too few large-scale comparative studies. For future trials, we recommend to assess comorbidities, quality of life, symptoms and signs with standardized tools and attempt to better define responder profiles to specific drug treatments.

"This book provides a complete review of the pharmacology of pain, including mechanisms of drug actions, clinical aspects of drug use, and new developments. It describes the different systems involved in the perception, transmission, and modulation of pain and discusses the available options for pharmacological treatment of pain"--Provided by publisher.

Abstract
Background: Chronic pain can often occur after surgery, substantially impairing patients' health and quality of life. It is caused by complex mechanisms that are not yet well understood. The predictable nature of most surgical procedures has allowed for the conduct of randomized controlled trials of pharmacological interventions aimed at preventing chronic postsurgical pain.

Objectives: The primary objective was to evaluate the efficacy of systemic drugs for the prevention of chronic pain after surgery by examining the proportion of patients reporting pain three months or more after surgery. The secondary objective was to evaluate the safety of drugs administered for the prevention of chronic pain after surgery.

Search methods: We identified randomized controlled trials (RCTs) of various systemically administered drugs for the prevention of chronic pain after surgery from CENTRAL, MEDLINE, EMBASE and handsearches of other reviews and trial registries. The most recent search was performed on 17 July 2013.

Selection criteria: Included studies were double-blind, placebo-controlled, randomized trials involving adults and evaluating one or more drugs administered systemically before, during or after surgery, or both, which measured pain three months or more after surgery.

Data collection and analysis: Data collected from each study included the study drug name, dose, route, timing and duration of dosing; surgical procedure; proportion of patients reporting any pain three months or more after surgery, reporting at least 4/10 or moderate to severe pain three months or more after surgery; and proportion of participants dropping out of the study due to treatment-emergent adverse effects.

Main results: We identified 40 RCTs of various pharmacological interventions including intravenous ketamine (14 RCTs), oral gabapentin (10 RCTs), oral pregabalin (5 RCTs), non-steroidal anti-inflammatories (3 RCTs), intravenous steroids (3 RCTs), oral N-methyl-D-aspartate (NMDA) blockers (3 RCTs), oral mexiletine (2 RCTs), intravenous fentanyl (1 RCT), intravenous lidocaine (1 RCT), oral venlafaxine (1 RCT) and inhaled nitrous oxide (1 RCT). Meta-analysis suggested a modest but statistically significant reduction in the incidence of chronic pain after surgery following treatment with ketamine but not gabapentin or pregabalin. Results with ketamine should be viewed with caution since most of the included trials were small (that is < 100 participants per treatment arm), which could lead to the overestimation of treatment effect.

Authors' conclusions: Additional evidence from better, well designed, large-scale trials is needed in order to more rigorously evaluate pharmacological interventions for the prevention of chronic pain after surgery. Furthermore, available evidence does not support the efficacy of gabapentin, pregabalin, non-steroidal anti-inflammatories, intravenous steroids, oral NMDA blockers, oral mexiletine, intravenous fentanyl, intravenous lidocaine, oral venlafaxine or inhaled nitrous oxide for the prevention of chronic postoperative pain.

Abstract
The average age of the world's population is increasing rapidly, with those over 80 years of age the fastest growing subsection of older persons. Consequently, a higher proportion of those presenting for surgery in the future will be older, including greater numbers aged over 100 years. Management of postoperative pain in these patients can be complicated by factors such as age and disease-related changes in physiology, and disease-drug and drug-drug interactions. There are also variations in pain perception and ways in which pain should be assessed, including in patients with cognitive impairment. Alterations in pharmacokinetics and pharmacodynamics may influence drugs and techniques used for pain relief. The evidence-base for postoperative pain management in the older population remains limited. However, most commonly used analgesic regimens are suitable for older patients if adapted and titrated appropriately.

Abstract
The Neuropathic Pain Special Interest Group of the International Association for the Study of Pain recently sponsored the development of evidence-based guidelines for the pharmacological treatment of neuropathic pain. Tricyclic antidepressants, dual reuptake inhibitors of serotonin and norepinephrine, calcium channel alpha(2)-delta ligands (ie, gabapentin and pregabalin), and topical lidocaine were recommended as first-line treatment options on the basis of the results of randomized clinical trials. Opioid analgesics and tramadol were recommended as second-line treatments that can be considered for first-line use in certain clinical circumstances. Results of several recent clinical trials have become available since the development of these guidelines. These studies have examined botulinum toxin, high-concentration capsaicin patch, lacosamide, selective serotonin reuptake inhibitors, and combination therapies in various neuropathic pain conditions. The increasing number of negative clinical trials of pharmacological treatments for neuropathic pain and ambiguities in the interpretation of these negative trials must also be considered in developing treatment guidelines. The objectives of the current article are to review the Neuropathic Pain Special Interest Group guidelines for the pharmacological management of neuropathic pain and to provide a brief overview of these recent studies.

Abstract
Background: New drug treatments, clinical trials, and standards of quality for assessment of evidence justify an update of evidence-based recommendations for the pharmacological treatment of neuropathic pain. Using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE), we revised the Special Interest Group on Neuropathic Pain (NeuPSIG) recommendations for the pharmacotherapy of neuropathic pain based on the results of a systematic review and meta-analysis.

Methods: Between April, 2013, and January, 2014, NeuPSIG of the International Association for the Study of Pain did a systematic review and meta-analysis of randomised, double-blind studies of oral and topical pharmacotherapy for neuropathic pain, including studies published in peer-reviewed journals since January, 1966, and unpublished trials retrieved from ClinicalTrials.gov and websites of pharmaceutical companies. We used number needed to treat (NNT) for 50% pain relief as a primary measure and assessed publication bias; NNT was calculated with the fixed-effects Mantel-Haenszel method.

Findings: 229 studies were included in the meta-analysis. Analysis of publication bias suggested a 10% overstatement of treatment effects. Studies published in peer-reviewed journals reported greater effects than did unpublished studies (r(2) 9·3%, p=0·009). Trial outcomes were generally modest: in particular, combined NNTs were 6·4 (95% CI 5·2-8·4) for serotonin-noradrenaline reuptake inhibitors, mainly including duloxetine (nine of 14 studies); 7·7 (6·5-9·4) for pregabalin; 7·2 (5·9-9·21) for gabapentin, including gabapentin extended release and enacarbil; and 10·6 (7·4-19·0) for capsaicin high-concentration patches. NNTs were lower for tricyclic antidepressants, strong opioids, tramadol, and botulinum toxin A, and undetermined for lidocaine patches. Based on GRADE, final quality of evidence was moderate or high for all treatments apart from lidocaine patches; tolerability and safety, and values and preferences were higher for topical drugs; and cost was lower for tricyclic antidepressants and tramadol. These findings permitted a strong recommendation for use and proposal as first-line treatment in neuropathic pain for tricyclic antidepressants, serotonin-noradrenaline reuptake inhibitors, pregabalin, and gabapentin; a weak recommendation for use and proposal as second line for lidocaine patches, capsaicin high-concentration patches, and tramadol; and a weak recommendation for use and proposal as third line for strong opioids and botulinum toxin A. Topical agents and botulinum toxin A are recommended for peripheral neuropathic pain only.

Interpretation: Our results support a revision of the NeuPSIG recommendations for the pharmacotherapy of neuropathic pain. Inadequate response to drug treatments constitutes a substantial unmet need in patients with neuropathic pain. Modest efficacy, large placebo responses, heterogeneous diagnostic criteria, and poor phenotypic profiling probably account for moderate trial outcomes and should be taken into account in future studies.

Funding: NeuPSIG of the International Association for the Study of Pain.

Abstract
Neuropathic pain caused by a lesion or disease of the somatosensory nervous system is a common chronic pain condition with major impact on quality of life. Examples include trigeminal neuralgia, painful polyneuropathy, postherpetic neuralgia, and central poststroke pain. Most patients complain of an ongoing or intermittent spontaneous pain of, for example, burning, pricking, squeezing quality, which may be accompanied by evoked pain, particular to light touch and cold. Ectopic activity in, for example, nerve-end neuroma, compressed nerves or nerve roots, dorsal root ganglia, and the thalamus may in different conditions underlie the spontaneous pain. Evoked pain may spread to neighboring areas, and the underlying pathophysiology involves peripheral and central sensitization. Maladaptive structural changes and a number of cell-cell interactions and molecular signaling underlie the sensitization of nociceptive pathways. These include alteration in ion channels, activation of immune cells, glial-derived mediators, and epigenetic regulation. The major classes of therapeutics include drugs acting on α2δ subunits of calcium channels, sodium channels, and descending modulatory inhibitory pathways.

Abstract
Aim: A recently published randomized study failed to show a significant reduction of phantom limb pain after perioperative epidural analgesia EDA [9]. Since these findings were not supported by previous studies,we conducted an analysis of factors contributing to the results of phantom limb pain prophylaxis. We calculated the efficacy of perioperative EDA as "Number Needed to Treat" (NNT).

Methods: Included studies were retrieved by a medline-search from 1966 to 1999 and published articles on phantom limb pain prophylaxis. First,we analyzed the influence of patient data, type of intervention and study design on the results. Then,we stratified studies in comparable groups and outcome measures. The efficacy of perioperative EDA in phantom limb pain prophylaxis was calculated using NNT's. The outcome criterion in this analysis was "free of phantom limb pain < or = 3 on an analogue scale from 0 ( no pain) to 10 (worst pain) 12 months after amputation".

Results: Variations in preoperative pain, start and duration of regional analgesia and the definition of phantom limb pain were associated with different results. After stratifying the results by the above mentioned definition of phantom pain intensity, only time and duration of regional analgesia showed effects on the study results. Pre-, intra- and postoperative EDA was associated with a significant reduction of phantom limb pain 12 months after amputation, NNT = 5,8 (95%-CI 3,2-28,6). However, a reduction of phantom limb pain by postoperative EDA alone could not be confirmed on the basis of the analysed data.

Conclusions: Perioperative EDA has been shown to be an effective prophylaxis of phantom limb pain. The most important differences between studies were the definition of phantom limb pain by intensity ratings. Thus, perioperative EDA does not completely abolish phantom limb pain, but increases the number of patients with a mild form of phantom pain.

Abstract
The actual incidence of neurological dysfunction resulting from haemorrhagic complications associated with neuraxial block is unknown. Although the incidence cited in the literature is estimated to be <1 in 150,000 epidural and <1 in 220,000 spinal anaesthetics, recent surveys suggest that the frequency is increasing and may be as high as 1 in 3000 in some patient populations. Overall, the risk of clinically significant bleeding increases with age, associated abnormalities of the spinal cord or vertebral column, the presence of an underlying coagulopathy, difficulty during needle placement, and an indwelling neuraxial catheter during sustained anticoagulation (particularly with standard unfractionated heparin or low molecular weight heparin). The decision to perform spinal or epidural anaesthesia/analgesia and the timing of catheter removal in a patient receiving antithrombotic therapy is made on an individual basis, weighing the small, although definite risk of spinal haematoma with the benefits of regional anaesthesia for a specific patient. Coagulation status should be optimized at the time of spinal or epidural needle/catheter placement, and the level of anticoagulation must be carefully monitored during the period of neuraxial catheterization. Indwelling catheters should not be removed in the presence of therapeutic anticoagulation, as this appears to significantly increase the risk of spinal haematoma. Vigilance in monitoring is critical to allow early evaluation of neurological dysfunction and prompt intervention. An understanding of the complexity of this issue is essential to patient management.

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The number of patients in buprenorphine opioid substitution therapy (BOST) or methadone opioid substitution therapy (MOST) programs is increasing. If these patients require surgery, it is generally agreed that methadone should be continued perioperatively. While some also recommend that buprenorphine is continued, concerns that it may limit the analgesic effectiveness of full mu-opioid agonists have led others to suggest that it should cease before surgery. However, no good evidence exists for either course of action. Therefore, we undertook a retrospective cohort study comparing pain relief and opioid requirements in the first 24 hours after surgery in 22 BOST and 29 MOST patients prescribed patient-controlled analgesia.

Abstract
Despite the increasing use of a variety of different analgesic strategies, opioids continue as the mainstay for management of moderate to severe acute pain. However concerns remain about their potential adverse effects on ventilation. The most commonly used term, respiratory depression, only describes part of that risk. Opioid-induced ventilatory impairment (OIVI) is a more complete term encompassing opioid-induced central respiratory depression (decreased respiratory drive), decreased level of consciousness (sedation) and upper airway obstruction, all of which, alone or in combination, may result in decreased alveolar ventilation and increased arterial carbon dioxide levels. Concerns about OIVI are warranted, as deaths related to opioid administration in the acute pain setting continue to be reported. Risks are often said to be higher in patients with obstructive sleep apnoea. However, the tendency to use the term 'obstructive sleep apnoea' to encompass the much broader spectrum of sleep- and obesity-related hypoventilation syndromes and the related misuse of terminology in papers relating to obstructive sleep apnoea and sleep-disordered breathing remain significant problems in discussions of opioid-related effects. Opioids given for management of acute pain must be titrated to effect for each patient. However strategies aiming for better pain scores alone, without highlighting the need for appropriate monitoring of OIVI, can and will lead to an increase in adverse events. Therefore, all patients must be monitored appropriately for OIVI (at the very least using sedation scores as a '6th vital sign') so that it can be detected at an early stage and appropriate interventions triggered.

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Abstract
A number of different treatments for neuropathic pain have been studied, but the literature is sizable, rapidly evolving, and lacks important information about practical aspects of patient management. Under the auspices of the International Association for the Study of Pain (IASP) Neuropathic Pain Special Interest Group (NeuPSIG), a consensus process was used to develop evidence-based guidelines for the pharmacologic management of neuropathic pain that take into account clinical efficacy, adverse effects, impact on health-related quality of life, convenience, and costs. On the basis of randomized clinical trials, medications recommended as first-line treatments for neuropathic pain included certain antidepressants (i.e., tricyclic antidepressants and dual reuptake inhibitors of both serotonin and norepinephrine), calcium channel alpha(2)-delta ligands (i.e., gabapentin and pregabalin), and topical lidocaine. Opioid analgesics and tramadol were recommended as second-line treatments that can be considered for first-line use in selected clinical circumstances. Other medications that generally would be used as third-line treatments include certain other antidepressant and antiepileptic medications, topical capsaicin, mexiletine, and N-methyl-d-aspartate receptor antagonists. Two other national and international associations recently published pharmacologic treatment guidelines for neuropathic pain, which are summarized and contrasted with the NeuPSIG recommendations. Recent guidelines for the use of neurostimulation for the treatment of neuropathic pain also are summarized. For all treatments for neuropathic pain, long-term studies, head-to-head comparisons, and studies of treatment combinations are a priority for future research.

Abstract
Objective: To quantify benefit and harm of epidural analgesia, compared with systemic opioid analgesia, in adults having surgery under general anesthesia.

Background: It remains controversial whether adding epidural analgesia to general anesthesia decreases postoperative morbidity and mortality.

Methods: We searched CENTRAL, EMBASE, PubMed, CINAHL, and BIOSIS till July 2012. We included randomized controlled trials comparing epidural analgesia (with local anesthetics, lasting for ≥ 24 hours postoperatively) with systemic analgesia in adults having surgery under general anesthesia, and reporting on mortality or any morbidity endpoint.

Results: A total of 125 trials (9044 patients, 4525 received epidural analgesia) were eligible. In 10 trials (2201 patients; 87 deaths), reporting on mortality as a primary or secondary endpoint, the risk of death was decreased with epidural analgesia (3.1% vs 4.9%; odds ratio, 0.60; 95% confidence interval, 0.39-0.93). Epidural analgesia significantly decreased the risk of atrial fibrillation, supraventricular tachycardia, deep vein thrombosis, respiratory depression, atelectasis, pneumonia, ileus, and postoperative nausea and vomiting, and also improved recovery of bowel function, but significantly increased the risk of arterial hypotension, pruritus, urinary retention, and motor blockade. Technical failures occurred in 6.1% of patients.

Conclusions: In adults having surgery under general anesthesia, concomitant epidural analgesia reduces postoperative mortality and improves a multitude of cardiovascular, respiratory, and gastrointestinal morbidity endpoints compared with patients receiving systemic analgesia. Because adverse effects and technical failures cannot be ruled out, individual risk-benefit analyses and professional care are recommended.

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